Tucatinib Combination Treatment After Trastuzumab-Deruxtecan in Patients With ERBB2-Positive Metastatic Breast Cancer.

Importance: Little is known regarding the outcomes associated with tucatinib combined with trastuzumab and capecitabine (TTC) after trastuzumab-deruxtecan exposure among patients with ERBB2 (previously HER2)-positive metastatic breast cancer (MBC). Objective: To investigate outcomes following TTC treatment in patients with ERBB2-positive MBC who had previously received trastuzumab-deruxtecan. Design, Setting, and Participants: This cohort study included all patients with MBC who were treated in 12 French comprehensive cancer centers between August 1, 2020, and December 31, 2022. Exposure: Tucatinib combined with trastuzumab and capecitabine administered at the recommended dose. Main Outcomes and Measures: Clinical end points included progression-free survival (PFS), time to next treatment (TTNT), overall survival (OS), and overall response rate (ORR). Results: A total of 101 patients with MBC were included (median age, 56 [range, 31-85] years). The median number of prior treatment lines for metastatic disease at TTC treatment initiation was 4 (range, 2-15), including 82 patients (81.2%) with previous trastuzumab and/or pertuzumab and 94 (93.1%) with previous ado-trastuzumab-emtansine) exposure. The median duration of trastuzumab-deruxtecan treatment was 8.9 (range, 1.4-25.8) months, and 82 patients (81.2%) had disease progression during trastuzumab-deruxtecan treatment, whereas 18 (17.8%) had stopped trastuzumab-deruxtecan for toxic effects and 1 (1.0%) for other reasons. Tucatinib combined with trastuzumab and capecitabine was provided as a third- or fourth-line treatment in 37 patients (36.6%) and was the immediate treatment after trastuzumab-deruxtecan in 86 (85.1%). With a median follow-up of 11.6 (95% CI, 10.5-13.4) months, 76 of 101 patients (75.2%) stopped TTC treatment due to disease progression. The median PFS was 4.7 (95% CI, 3.9-5.6) months; median TTNT, 5.2 (95% CI, 4.5-7.0) months; and median OS, 13.4 (95% CI, 11.1 to not reached [NR]) months. Patients who received TTC immediately after trastuzumab-deruxtecan had a median PFS of 5.0 (95% CI, 4.2-6.0) months; median TTNT of 5.5 (95% CI, 4.8-7.2) months, and median OS of 13.4 (95% CI, 11.9-NR) months. Those who received TTC due to trastuzumab-deruxtecan toxicity-related discontinuation had a median PFS of 7.3 (95% CI, 3.0-NR) months. Best ORR was 29 of 89 patients (32.6%). Sixteen patients with active brain metastasis had a median PFS of 4.7 (95% CI, 3.0-7.3) months, median TTNT of 5.6 (95% CI, 4.4 to NR), and median OS of 12.4 (95% CI, 8.3-NR) months. Conclusions and Relevance: In this study, TTC therapy was associated with clinically meaningful outcomes in patients with ERBB2-positive MBC after previous trastuzumab-deruxtecan treatment, including those with brain metastases. Prospective data on optimal drug sequencing in this rapidly changing therapeutic landscape are needed.

A novel Fc-engineered cathepsin D-targeting antibody enhances ADCC, triggers tumor-infiltrating NK cell recruitment, and improves treatment with paclitaxel and enzalutamide in triple-negative breast cancer.

INTRODUCTION: Triple-negative breast cancer (TNBC) prognosis is poor. Immunotherapies to enhance the antibody-induced natural killer (NK) cell antitumor activity are emerging for TNBC that is frequently immunogenic. The aspartic protease cathepsin D (cath-D), a tumor cell-associated extracellular protein with protumor activity and a poor prognosis marker in TNBC, is a prime target for antibody-based therapy to induce NK cell-mediated antibody-dependent cellular cytotoxicity (ADCC). This study investigated whether Fc-engineered anti-cath-D antibodies trigger ADCC, their impact on antitumor efficacy and tumor-infiltrating NK cells, and their relevance for combinatory therapy in TNBC. METHODS: Cath-D expression and localization in TNBC samples were evaluated by western blotting, immunofluorescence, and immunohistochemistry. The binding of human anti-cath-D F1M1 and Fc-engineered antibody variants, which enhance (F1M1-Fc+) or prevent (F1M1-Fc-) affinity for CD16a, to secreted human and murine cath-D was analyzed by ELISA, and to CD16a by surface plasmon resonance and flow cytometry. NK cell activation was investigated by flow cytometry, and ADCC by lactate dehydrogenase release. The antitumor efficacy of F1M1 Fc-variants was investigated using TNBC cell xenografts in nude mice. NK cell recruitment, activation, and cytotoxic activity were analyzed in MDA-MB-231 cell xenografts by immunophenotyping and RT-qPCR. NK cells were depleted using an anti-asialo GM1 antibody. F1M1-Fc+ antitumor effect was assessed in TNBC patient-derived xenografts (PDXs) and TNBC SUM159 cell xenografts, and in combination with paclitaxel or enzalutamide. RESULTS: Cath-D expression on the TNBC cell surface could be exploited to induce ADCC. F1M1 Fc-variants recognized human and mouse cath-D. F1M1-Fc+ activated NK cells in vitro and induced ADCC against TNBC cells and cancer-associated fibroblasts more efficiently than F1M1. F1M1-Fc- was ineffective. In the MDA-MB-231 cell xenograft model, F1M1-Fc+ displayed higher antitumor activity than F1M1, whereas F1M1-Fc- was less effective, reflecting the importance of Fc-dependent mechanisms in vivo. F1M1-Fc+ triggered tumor-infiltrating NK cell recruitment, activation and cytotoxic activity in MDA-MB-231 cell xenografts. NK cell depletion impaired F1M1-Fc+ antitumor activity, demonstrating their key role. F1M1-Fc+ inhibited growth of SUM159 cell xenografts and two TNBC PDXs. In combination therapy, F1M1-Fc+ improved paclitaxel and enzalutamide therapeutic efficacy without toxicity. CONCLUSIONS: F1M1-Fc+ is a promising immunotherapy for TNBC that could be combined with conventional regimens, including chemotherapy or antiandrogens.

First evidence of AXL expression on circulating tumor cells in metastatic breast cancer patients: A proof-of-concept study.

BACKGROUND: For several years, the AXL tyrosine kinase receptor, a member of the Tyro3-Axl-Mer (TAM) family, has been considered a new strategic target in oncology. AXL overexpression is common in solid tumors and is associated with poor prognosis. In this context, the detection of a subset of circulating tumor cells (CTCs) that express AXL (AXL+ CTCs) could be clinically relevant. METHODS: Immunostaining was performed to assess AXL expression in human breast cancer cell lines. The optimal conditions were established using flow cytometry. Spiking experiments were carried out to optimize the parameters of the CellSearch® system detection test. CTC enumeration and AXL expression were evaluated in patients with metastatic breast cancer (mBC) before treatment initiation. RESULTS: An innovative AXL+ CTC detection assay to be used with the CellSearch® system was developed. In a prospective longitudinal clinical trial, blood samples from 60 patients with untreated mBC were analyzed to detect AXL+ CTCs with this new assay. CTCs were detected in 35/60 patients (58.3%) and AXL+ CTCs were identified in 7 of these 35 patients (11.7% of all patients). CONCLUSION: This newly established AXL+ CTC assay is a promising tool that can be used for liquid biopsy in future clinical trials to stratify and monitor patients with cancer receiving anti-AXL therapies.

Anti-cathepsin D immunotherapy triggers both innate and adaptive anti-tumour immunity in breast cancer.

BACKGROUND AND PURPOSE: Triple-negative breast cancer (TNBC) has poorer outcomes than other breast cancers (BC), including HER2+ BC. Cathepsin D (CathD) is a poor prognosis marker overproduced by BC cells, hypersecreted in the tumour microenvironment with tumour-promoting activity. Here, we characterized the immunomodulatory activity of the anti-CathD antibody F1 and its improved Fab-aglycosylated version (F1M1) in immunocompetent mouse models of TNBC (C57BL/6 mice harbouring E0771 cell grafts) and HER2-amplified BC (BALB/c mice harbouring TUBO cell grafts). EXPERIMENTAL APPROACH: CathD expression was evaluated by western blotting and immunofluorescence, and antibody binding to CathD by ELISA. Antibody anti-tumour efficacy was investigated in mouse models. Immune cell recruitment and activation were assessed by immunohistochemistry, immunophenotyping, and RT-qPCR. KEY RESULTS: F1 and F1M1 antibodies remodelled the tumour immune landscape. Both antibodies promoted innate antitumour immunity by preventing the recruitment of immunosuppressive M2-polarized tumour-associated macrophages (TAMs) and by activating natural killer cells in the tumour microenvironment of both models. This translated into a reduction of T-cell exhaustion markers in the tumour microenvironment that could be locally supported by enhanced activation of anti-tumour antigen-presenting cell (M1-polarized TAMs and cDC1 cells) functions. Both antibodies inhibited tumour growth in the highly-immunogenic E0771 model, but only marginally in the immune-excluded TUBO model, indicating that anti-CathD immunotherapy is more relevant for BC with a high immune cell infiltrate, as often observed in TNBC. CONCLUSION AND IMPLICATION: Anti-CathD antibody-based therapy triggers the anti-tumour innate and adaptive immunity in preclinical models of BC and is a promising immunotherapy for immunogenic TNBC.

Pertuzumab Plus Trastuzumab With or Without Chemotherapy Followed by Emtansine in ERBB2-Positive Metastatic Breast Cancer: A Secondary Analysis of a Randomized Clinical Trial.

Importance: In ERBB2 (formerly HER2)-positive metastatic breast cancer (MBC), combining trastuzumab and pertuzumab with taxane-based chemotherapy is the first line of standard care. Given that trastuzumab plus pertuzumab was proven effective in ERBB2-positive MBC, even without chemotherapy, whether the optimal first-line strategy could be trastuzumab plus pertuzumab alone instead of with chemotherapy is unresolved. Objective: To assess overall survival (OS) at 2 years and progression-free survival (PFS) for patients randomly assigned to receive first-line pertuzumab plus trastuzumab alone or with chemotherapy followed by trastuzumab and emtansine at progression; PFS of second-line trastuzumab and emtansine treatment following trastuzumab plus pertuzumab; and OS and PFS in the ERBB2-enriched and ERBB2-nonenriched subtypes. Design, Setting, and Participants: This was a secondary analysis of a multicenter, open-label, phase 2 randomized clinical trial conducted at 27 sites in France, 20 sites in Switzerland, 9 sites in the Netherlands, and 1 site in Germany. Overall, 210 patients with centrally confirmed ERBB2-positive MBC were randomized between May 3, 2013, and January 4, 2016, with termination of the trial May 26, 2020. Data were analyzed from December 18, 2020, to May 10, 2022. Interventions: Patients randomly received pertuzumab (840 mg intravenously [IV], then 420 mg IV every 3 weeks) plus trastuzumab (8 mg/kg IV, then 6 mg/kg IV every 3 weeks) without chemotherapy (group A) or pertuzumab plus trastuzumab (same doses) with either paclitaxel (90 mg/m2 for days 1, 8, and 15, then every 4 weeks for ≥4 months) or vinorelbine tartrate (25 mg/m2 for first administration followed by 30 mg/m2 on days 1 and 8 and every 3 weeks for ≥4 months) followed by pertuzumab plus trastuzumab maintenance after chemotherapy discontinuation (group B). Main Outcomes and Measures: Overall survival at 24 months by treatment group, PFS for first-line treatment, PFS for second-line treatment, and patient-reported quality of life (QOL). Results: A total of 210 patients were included in the analysis, with a median age of 58 (range, 26-85) years. For group A, 24-month OS was 79.0% (90% CI, 71.4%-85.4%); for group B, 78.1% (90% CI, 70.4%-84.5%). Median PFS with first-line treatment was 8.4 (95% CI, 7.9-12.0) months in group A and 23.3 (95% CI, 18.9-33.1) months in group B. Unlike expectations, OS and PFS did not markedly differ between populations with ERBB2-enriched and ERBB2-nonenriched cancer. Adverse events were less common without chemotherapy, with small QOL improvements from baseline in group A and stable QOL in group B. Conclusions and Relevance: The findings of this secondary analysis of a randomized clinical trial suggest that the chemotherapy-free anti-ERBB2 strategy is feasible without being detrimental in terms of OS. The 50-gene prediction analysis of microarray signature could not help to identify the most appropriate patient population for this approach. Trial Registration: ClinicalTrials.gov Identifier: NCT01835236.

Long-Term Results with Everolimus in Advanced Hormone Receptor Positive Breast Cancer in a Multicenter National Real-World Observational Study.

Everolimus is the first oral targeted therapy widely used in advanced HR+/HER2- breast cancer. We sought to evaluate the impact of everolimus-based therapy on overall survival in the ESME-MBC database, a national metastatic breast cancer cohort that collects retrospective data using clinical trial-like methodology including quality assessments. We compared 1693 patients having received everolimus to 5928 patients not exposed to everolimus in the same period. Overall survival was evaluated according to treatment line, and a propensity score with the inverse probability of treatment weighting method was built to adjust for differences between groups. Crude and landmark overall survival analyses were all compatible with a benefit from everolimus-based therapy. Adjusted hazard ratios for overall survival were 0.34 (95% CI: 0.16-0.72, p = 0.0054), 0.34 (95% CI: 0.22-0.52, p < 0.0001), and 0.23 (95% CI: 0.14-0.36, p < 0.0001) for patients treated with everolimus in line 1, 2, and 3 and beyond, respectively. No clinically relevant benefit on progression-free survival was observed. Causes for everolimus discontinuation were progressive disease (56.2%), adverse events (27.7%), and other miscellaneous reasons. Despite the limitations inherent to such retrospective studies, these results suggest that adding everolimus-based therapy to the therapeutic sequences in patients with advanced HR+/HER2- breast cancer may favorably affect overall survival.

Hypnosis on patients treated with adjuvant chemotherapy for breast cancer: A feasibility study.

BACKGROUND: Acceptability and tolerance of chemotherapy on patients treated for breast cancer remain challenging. Complementary approaches such as hypnosis may have a favorable impact both at the time of announcing and during chemotherapy, due to the notorious anxiety, distress, and self-perceived dysfunction. The objective of the study was that the patients complied with at least four self-hypnosis sessions out of the six cycles of chemotherapy. METHODS: This open, prospective longitudinal study assessed feasibility of compliance to self-hypnosis during chemotherapy in an outpatients setting. Training sessions were given by a hypnotherapist. Throughout each cycle of chemotherapy, the patient had to use self-hypnosis to better control her anxiety or any difficulties. Nurses could offer help to the patient. Chemotherapy-associated side effects were evaluated through the NCI-Common Toxicity Criteria for Adverse Events v 4.03; moreover, side effects as pain, nausea, vomiting, fatigue, and anxiety were also evaluated during chemotherapy using a visual analogic scale. Health-related quality of life, emotional distress (anxiety and depression), and cancer-related fatigue were assessed (at inclusion, end of chemotherapy and 3 months later) using the EORTC QLQ-C30 and QLQ-BR23, HADS and MFI-20 questionnaires, respectively. The number of patients screened and actually included in the study was reported, as the reasons for refusal. RESULTS: Thirty-five patients were included with a median age of 55 years (35-78). All patients received a hypnosis training session. The overall compliance with self-hypnosis was 68.6% (95% CI: 50.7%-83.2%), meaning that more than two thirds of patients performed at least four sessions of self-hypnosis. According to NCI-CTCAE, Grade 2 nausea and vomiting was observed in 45.7% and 22.9%, respectively, Grade 2 fatigue in 62.9%. Based on the HADS questionnaire, anxiety increased at the end of the chemotherapy and returned to the initial value 3 months later (p = .97) whereas depression significantly decrease 3 months after the end of chemotherapy with respect to the inclusion (p = .003). Role, emotional, and cognitive functioning were slightly affected throughout the treatment, in contrast to dyspnea or physical functioning. CONCLUSION: Our study showed that self-hypnosis was feasible on patients newly diagnosed for breast cancer receiving chemotherapy.

SPARC in cancer-associated fibroblasts is an independent poor prognostic factor in non-metastatic triple-negative breast cancer and exhibits pro-tumor activity.

Triple-negative breast cancer (TNBC) is the most aggressive breast cancer subtype and lacks specific targeted therapeutic agents. The current mechanistic evidence from cell-based studies suggests that the matricellular protein SPARC has a tumor-promoting role in TNBC; however, data on the clinical relevance of SPARC expression/secretion by tumor and stromal cells in TNBC are limited. Here, we analyzed by immunohistochemistry the prognostic value of tumor and stromal cell SPARC expression in 148 patients with non-metastatic TNBC and long follow-up (median: 5.4 years). We also quantified PD-L1 and PD-1 expression. We detected SPARC expression in tumor cells (42.4%), cancer-associated fibroblasts (CAFs; 88.1%), tumor-associated macrophages (77.1%), endothelial cells (75.2%) and tumor-infiltrating lymphocytes (9.8%). Recurrence-free survival was significantly lower in patients with SPARC-expressing CAFs. Multivariate analysis showed that SPARC expression in CAFs was an independent prognostic factor. We also detected tumor and stromal cell SPARC expression in TNBC cytosols, and in patient-derived xenografts and cell lines. Furthermore, we analyzed publicly available single-cell mRNA sequencing data and found that in TNBC, SPARC is expressed by different CAF subpopulations, including myofibroblasts and inflammatory fibroblasts that are involved in tumor-related processes. We then showed that fibroblast-secreted SPARC had a tumor-promoting role by inhibiting TNBC cell adhesion and stimulating their motility and invasiveness. Overall, our study demonstrates that SPARC expression in CAFs is an independent prognostic marker of poor outcome in TNBC. Patients with SPARC-expressing CAFs could be eligible for anti-SPARC targeted therapy.

Emotional processes in partners' quality of life at various stages of breast cancer pathway: a longitudinal study.

INTRODUCTION: Several studies have shown that emotional competence (EC) impacts cancer adjustment via anxiety and depression symptoms. The objective was to test this model for the quality of life (QoL) of partners: first, the direct effect of partners' EC on their QoL, anxiety and depression symptoms after cancer diagnosis (T1), after chemotherapy (T2) and after radiotherapy (T3); Second, the indirect effects of partners' EC at T1 on their QoL at T2 and T3 through anxiety and depression symptoms. METHODS: 192 partners of women with breast cancer completed a questionnaire at T1, T2 and T3 to assess their EC (PEC), anxiety and depression symptoms (HADS) and QoL (Partner-YW-BCI). Partial correlations and regression analyses were performed to test direct and indirect effects of EC on issues. RESULTS: EC at T1 predicted fewer anxiety and depression symptoms at each time and all dimensions of QoL, except for career management and financial difficulties. EC showed different significant indirect effects (i.e. via anxiety or depression symptoms) on all sub-dimensions of QoL, except for financial difficulties, according to the step of care pathway (T2 and T3). Anxiety and depression played a different role in the psychological processes that influence QoL. CONCLUSION: Findings confirm the importance of taking emotional processes into account in the adjustment of partners, especially regarding their QoL and the support they may provide to patients. It, thus, seems important to integrate EC in future health models and psychosocial interventions focused on partners or caregivers.

Correlation of the TIGIT-PVR immune checkpoint axis with clinicopathological features in triple-negative breast cancer.

Background: T cell immunoreceptor with Ig and ITIM domains (TIGIT) interacts with poliovirus receptor (PVR) to contribute to cancer immune escape. Recently, TIGIT and PVR have been identified as promising immunotherapy targets. Their gene expression is upregulated in many solid tumors, but their protein expression level is not well documented, particularly in triple negative breast cancer (TNBC), the breast cancer subtype that most benefit from immunotherapy. Methods: TIGIT and PVR expression levels were assessed by immunohistochemistry in 243 surgically resected localized TNBC and then their relationship with clinical-pathological features and clinical outcome was analyzed. Results: TIGIT expression was observed in immune cells from the tumor microenvironment, whereas PVR was mainly expressed by tumor cells. High TIGIT expression was significantly associated with age (p=0.010), histological grade (p=0.014), non-lobular histology (p=0.024), adjuvant chemotherapy (p=0.006), and various immune cell populations (tumor infiltrating lymphocytes (TILs), CD3+, CD8+, PD-1+ cells; all p<0.0001), PD-L1+ tumor cells (p<0.0001), and PD-L1+ stromal cells (p=0.003). Infiltration by TIGIT+ cells tended to be higher in non-molecular apocrine tumors (p=0.088). PVR was significantly associated with histological grade (p<0.0001), the basal-like (p=0.003) and non-molecular apocrine phenotypes (p=0.039), high TILs infiltration (p=0.011), CD3+ (p=0.002), CD8+ (p=0.024) T cells, and PD-L1 expression in tumor (p=0.003) and stromal cells (p=0.001). In univariate analysis, only known prognostic factors (age, tumor size, lymph node status, adjuvant chemotherapy, TILs and CD3+ T-cell infiltrate) were significantly associated with relapse-free survival (RFS) and overall survival. High TIGIT and PVR expression levels tended to be associated with longer RFS (p=0.079 and 0.045, respectively). The analysis that included only non-molecular apocrine TNBC revealed longer RFS for tumors that strongly expressed TIGIT or PVR (p=0.025 for TIGIT and 0.032 for PVR). Conclusions: These results indicated that in TNBC, TIGIT+ cells can easily interact with PVR to exert their inhibitory effects. Their wide expression in TNBC and their association with other immune checkpoint components suggest the therapeutic interest of the TIGIT-PVR axis.

Association of Endocrine Therapy for HR+/ERBB2+ Metastatic Breast Cancer With Survival Outcomes.

Importance: Evidence suggests that patients with human epidermal growth factor receptor 2-positive (ERBB2+ [formerly HER2+]) metastatic breast cancer (MBC) have different clinical characteristics and outcomes according to their hormone receptor (HR) status. The place of endocrine therapy (ET) for patients with HR+/ERBB2+ is still not clearly defined in this setting. Objective: To evaluate the association of HR status and first-line inclusion of ET with outcomes among patients with ERBB2+ MBC. Design, Setting, and Participants: This cohort study was an analysis of clinical data from the French clinical Epidemiological Strategy and Medical Economics (ESME) cohort, including patients with MBC who started treatment between 2008 and 2017. The last date of follow-up was June 18, 2020. Data were analyzed from May 2021 to May 2022. Exposures: Patients were treated with first-line ERBB2-targeted therapy and either chemotherapy (CT) with or without ET or ET alone. For the study of the association of maintenance ET with outcomes, we included patients treated with first-line ERBB2-targeted therapy with CT and with or without maintenance ET. Main Outcomes and Measures: Median overall survival (OS) and median first-line progression-free survival (PFS) were reported using the Kaplan-Meier method. Cox proportional hazards models and a propensity score were constructed to report and adjust for prognostic factors. Multivariable analysis included age at MBC, time to MBC, number of metastatic sites, type of metastases, and Eastern Cooperative Oncology Group performance status. Results: Among 4145 women with ERBB2+ MBC, 2696 patients had HR+ (median [IQR] age, 58.0 [47.0-67.0] years) and 1449 patients had HR- (56.0 [47.0-64.0] years) tumors. The median OS for patients with HR+ vs HR- tumors was 55.9 months (95% CI, 53.7-59.4 months) vs 42.0 months (95% CI, 38.8-45.2 months), confirmed in multivariable analysis (hazard ratio, 1.40; 95% CI, 1.26-1.56; P < .001). The median PFS for patients with HR+ vs HR- tumors was 12.2 months (95% CI, 11.5-12.9 months) vs 9.8 months (95% CI, 9.2-11.0 months; P = .01), and the HR was 1.15 (95% CI, 1.06-1.26; P < .001). In multivariable analysis, no significant difference was found in OS or PFS for 1520 patients treated with ERBB2-targeted therapy with CT and with or without ET vs 203 patients receiving ERBB2-targeted therapy with ET, regardless of type of ERBB2-targeted therapy (trastuzumab or trastuzumab with pertuzumab). This result was confirmed by matching patients using a propensity score. Using the time-dependent ET variable among patients with ERBB2-targeted therapy with CT, those with maintenance ET had significantly better PFS (hazard ratio, 0.70; 95% CI, 0.60-0.82; P < .001) and OS (hazard ratio, 0.47; 95% CI, 0.39-0.57; P < .001). Conclusions and Relevance: These results suggest that ET-containing first-line regimens may be associated with benefits among a subgroup of patients with HR+/ERBB2+ MBC.

Efficacy of taxanes rechallenge in first-line treatment of early metastatic relapse of patients with HER2-negative breast cancer previously treated with a (neo)adjuvant taxanes regimen: A multicentre retrospective observational study.

BACKGROUND: Taxanes are one of the most effective chemotherapies (CT) in breast cancer (BC), but the efficacy of taxanes rechallenge in early metastatic relapse has been poorly studied in patients previously treated by taxanes in the (neo)adjuvant setting. Our study aimed to analyse the efficacy of taxane rechallenge in case of early metastatic relapse in a multicentre retrospective observational study compared with other chemotherapies. METHODS: We analysed the French national ESME metastatic BC (MBC) database and selected HER2- MBC patients who received CT in first-line treatment for a metastatic relapse occurring 3-24 months after previous (neo)adjuvant taxanes treatment. RESULTS: Of 23,501 female patients with MBC in ESME, 1057 met the selection criteria. 58.4% received a taxane-based regimen (75.4% concomitant bevacizumab) and 41.6% received other CT. In hormone-receptor positive (HR+)/HER2- MBC, multivariate analysis showed no difference in OS between taxanes without bevacizumab compared to other CT (HZR = 1.3 [0.97; 1.74], but taxanes was significantly associated with worse PFS (HZR = 1.48 [1.14; 1.93]). In TNBC, taxanes without bevacizumab and carboplatin/gemcitabine were not superior to other CT for OS (HZR = 1.07 [0.79; 1.44] and HZR = 0.81 [0.58; 1.13], respectively), while for PFS, taxanes was inferior (HZR = 1.33 [1.06-1.67]) and carboplatin plus gemcitabine was superior to other CT (HZR = 0.63 [0.46; 0.87]). For both subtypes, the worse outcome observed with paclitaxel was no longer observed with the addition of bevacizumab. CONCLUSIONS: With the limitation of retrospective design, taxanes rechallenge in early metastatic relapse of BC may result in a worse PFS in TNBC and HR+/HER2- MBC, which was not observed with the addition of bevacizumab.

Unusual Focal Lung Uptake without CT Abnormality on a Bone Scan: What Might It Mean?

A 48-year-old woman was referred for a bone scan as an assessment of bone metastasis from breast cancer. Surprisingly, two hot spots of lung uptake were present in the left lung without any abnormality on CT slices. No history of pulmonary disease was observed. An optimized CT scan with fine slices performed the same day was strictly normal (without any micronodule). A lung ventilation/perfusion scintigraphy showed no significant perfusion defect. A follow-up bone scan performed eight months later was normal and without any lung uptake. After exclusion of the main etiologies described in the literature, such as amylosis, sarcoidosis, abscess, or hypercalcemia, radiotracer microembolism seems to be the most likely hypothesis in this patient.

Pharmacokinetic Variability Drives Palbociclib-Induced Neutropenia in Metastatic Breast Cancer Patients: Drug-Drug Interactions Are the Usual Suspects.

Palbociclib is a good candidate for therapeutic drug monitoring (TDM) due to its narrow therapeutic range and frequency of toxicities, particularly high-grade neutropenia. In this prospective, bicentric clinical trial, we evaluated the palbociclib exposure−toxicity relationship and determined the relevant sources of palbociclib pharmacokinetic variability, including drug−drug interactions (DDI). We followed 58 patients (mean age: 62.9 years) for 1 year. The geometric median of palbociclib plasma trough concentration (Ctrough) was 74.1 ng/mL. Neutropenia occurred in 70.7% of patients (high grade in 67.2% of patients). High-grade neutropenia occurrence during the first two palbociclib cycles was higher in patients with lower neutrophil count at initiation (p = 0.002). Palbociclib plasma Ctrough was correlated with high-grade neutropenia occurrence during the first two cycles (p = 0.024, OR 5.51). Co-treatment with agents that may interfere with palbociclib PK significantly influenced palbociclib Ctrough (p < 0.05). CYP3A4/P-glycoprotein inhibitors increased by 25% palbociclib Ctrough (p = 0.035), while antacids reduced it by 20% (p = 0.036). However, DDI did not have any significant effect on high-grade neutropenia occurrence (p > 0.05). This study confirms the major role of TDM to manage palbociclib safe use from the first week of treatment, particularly the significant incidence of hematological toxicity. Moreover, this first dedicated prospective study confirmed the importance of characterizing co-treatments to limit the DDI risk with oral-targeted therapies.

Impact of lobular versus ductal histology on overall survival in metastatic breast cancer: a French retrospective multicentre cohort study.

BACKGROUND: The impact of the histological lobular subtype on overall survival (OS) in metastatic breast cancer (MBC) is still under debate, with very few data available. PATIENTS AND METHODS: Using the French national multicentre Epidemiological Strategy and Medico Economics [ESME]) data platform, the primary objective was to compare the OS of patients with invasive lobular carcinoma (ILC) versus invasive ductal carcinoma (IDC) MBC, with adjustment on the main prognostic factors using two approaches: multivariable analysis and matching with a propensity score. Secondary objectives were to compare first-line progression-free survival (PFS1) and describe patients and tumour characteristics. RESULTS: Of the 16,703 patients with MBC in the ESME database, 13,111 met all inclusion criteria for the present analysis. One-thousand eight-hundred and four (13.8%) patients had ILC and 11.307 (86.2%) IDC. In the multivariable analysis, patients with ILC had a worse OS [hazard ratio (HR): 1.31; 95%CI 1.20-1.42; p < 0.0001] and a worse PFS1 (HR: 1.15; 95%CI 1.07-1.22; p < 0.0001) as compared with those with IDC, independently of hormone receptor and HER2 status. Interestingly, OS was better (HR 0.79; 95% confidence interval [CI] 0.64-0.98; p = 0.0302), worse (HR: 1.17; 95%CI 1.08-1.27; p = 0.0001) or similar (HR: 0.88; 95%CI 0.67-1.15; p = 0.3455) in patients with ILC with triple-negative, hormone receptor-positive/HER2-negative and HER2-positive MBC, respectively, compared with patients with IDC. CONCLUSION: Lobular histology is an independent adverse prognostic factor among women with MBC. ILC MBC could be considered a specific entity. Dedicated prospective studies are needed to tailor the management of these patients.

Adjustment of young women with breast cancer after chemotherapy: A mediation model of emotional competence via emotional distress.

OBJECTIVE: Emotional competence (EC) is considered a substantial resource in the adjustment of cancer patients, especially via its effect on anxiety and depression symptoms. This research aimed at assessing the impact of intrapersonal EC in young women (≤45 years) with breast cancer (YWBC) on their specific quality of life (i.e. subjective experience related to daily difficulties and perceived repercussions of the disease and treatments) related to chemotherapy, via anxiety and depression symptoms. METHODS: Two hundred fifty YWBC from 24 French centers completed a self-reported questionnaire after diagnosis (T1) and after the chemotherapy phase (T2), comprising the Young Women Breast Cancer Inventory, the Profile of EC and the Hospital Anxiety and Depression Scale. The indirect effect of EC (T1) on subjective experience (T2) via anxiety and depression symptoms (T2) was tested using regressions and the Macro PROCESS. RESULTS: Emotional competence predicted fewer anxiety and depression symptoms at T1 and T2, and a better subjective experience at T2 via fewer anxiety and depression symptoms. Depression symptoms appeared to be a stronger mediator than anxiety symptoms on four dimensions (Support from close relatives, feeling of couple cohesion, body image and sexuality, management of children and everyday life), whereas anxiety symptoms appeared to be a stronger mediator on two dimensions (negative affectivity and apprehension about the future, deterioration of relationships). CONCLUSIONS: These results support the importance of developing psycho-affective interventions to reinforce the EC of YWBC during chemotherapy in order to facilitate the cognitive and emotional processes necessary for a better adjustment and subjective experience.

Real-world evidence of the management and prognosis of young women (⩽40 years) with de novo metastatic breast cancer.

Background: Breast cancer (BC) in young women merits a specific approach given the associated fertility, genetic and psychosocial issues. De novo metastatic breast cancer (MBC) in young women is an even more serious condition, with limited data available. Methods: We evaluated management of women aged ⩽40 years with de novo MBC in a real-life national multicentre cohort of 22,463 patients treated between 2008 and 2016 (NCT0327531). Our primary objective was to compare overall survival (OS) in young women versus women aged 41-69 years. The secondary objectives were to compare first-line progression-free survival (PFS1) and to describe treatment patterns. Results: Of the 4524 women included, 598 (13%) were ⩽40 years. Median age at MBC diagnosis was 36 years (range = 20-40). Compared with women aged 41-69 years, young women had more grade III tumours (49% versus 35.7%, p < 0.0001), human epidermal growth factor receptor 2 amplified (HER2+) disease (34.6% versus 26.4%, p < 0.0001) and HR-/HER2- disease known as "triple negative breast cancer" (TNBC) (17.1% versus 12.7%, p < 0.0001). BRCA testing was performed for 260 young women, with a BRCA1/2 mutation in 44 (17% of those tested) In young HR+/HER2- patients, chemotherapy (CT) was given as the frontline treatment more frequently compared with older ones (89.6% versus 68.8%, respectively, p < 0.0001). After median follow-up of 49.7 months (95% confidence interval, CI = 48.0-51.7), the median OS of young women was 58.5 months, 20.7 months and not attained in HR+/HER2-, TNBC and HER2+ subgroups, respectively. After adjustment for histological subtype, tumour grade, and number and type of metastasis, young women had significantly better OS compared with older ones, except for the TNBC subgroup, for which the outcome was similar. PFS1 was statistically different only in the TNBC subgroup, with 7.8 months for young women and 6.3 months for older women (p = 0.0015). Conclusion: De novo MBC affects a significant proportion of young women. A subgroup of these patients achieves long OS and merits multidisciplinary care.

Prognostic Value of HER2-Low Expression in Non-Metastatic Triple-Negative Breast Cancer and Correlation with Other Biomarkers.

HER2-low breast cancer (i.e., HER 1+ or 2+, without gene amplification) is an emerging subtype for which very few data are available, especially within the triple-negative breast cancer (TNBC) group. Our aim was to evaluate HER2 expression and its prognostic value in a large retrospective series of patients with non-metastatic TNBC (median age: 57.7 years; range: 28.5-98.6). Among the 296 TNBC samples, 83.8% were HER2 0, 13.5% were HER2 1+, and 2.7% were HER2 2+ (HercepTestTM and 2018 ASCO/CAP guidelines for HER2 scoring). CK5/6 and/or EGFR-expressing androgen receptors and FOXA1-expressing tumors were classified as basal-like (63.8%) and molecular apocrine-like (MA, 40.2%), respectively. Compared with HER2 0 tumors, HER2 1+/2+ tumors exhibited a lower histological grade (1/2) (35.4% vs. 18.2%, p = 0.007) and MA profile (57.5% vs. 36.7%, p = 0.008). Moreover, patients with HER2 1+/2+ tumors were older (p = 0.047). After a median follow-up of 9.7 years, HER2 2+ tumors (compared with HER2 0/1+ tumors) were associated with worse relapse-free survival (RFS) (HR = 3.16, 95% CI [1.27; 7.85], p = 0.034) in a univariate analysis. Overall survival (OS) and RFS were not different in the HER2 0 and 1+/2+ groups. HER2 levels were not significantly associated with OS or RFS in a multivariate analysis.

Changes in vitamin D and calcium metabolism markers in patients undergoing adjuvant chemotherapy for breast cancer.

BACKGROUND: Changes in calcium metabolism and calcium urinary excretion during chemotherapy have not been thoroughly assessed in patients with early breast cancer (EBC), a population who frequently present vitamin D insufficiency. As hypercalciuria is a classical contra-indication to vitamin D (VD) supplementation, this study evaluated changes in VD and calcium metabolism parameters in patients with EBC undergoing adjuvant chemotherapy (CT). METHODS: In patients with EBC who received six cycles of adjuvant CT, VD and calcium parameters were monitored at inclusion, and then every 3 weeks, at each CT cycle initiation. The primary endpoint was the percentage of patients showing hypercalciuria during adjuvant CT (between Day 1, Cycle 1 [D1C1] and Day 1, Cycle 6 [D1C6]). RESULTS: The primary endpoint could be evaluated in 82 patients. Most patients (n = 66, 80.5%) had VD insufficiency (< 30 ng/mL) at baseline. Hypercalciuria was detected in 29 patients (35.4%; 95% CI: 25.6-46.5) between D1C1 and D1C6, but was not clinically significant in any of the affected patients. The percentage of hypercalciuria events was not different between patients with sufficient and insufficient baseline VD levels (34.8% vs. 37.5%), and between patients who received or not VD supplementation (37.5% vs. 34.5%,). CONCLUSIONS: This comprehensive study on VD and calcium parameter changes in patients with EBC during adjuvant chemotherapy shows that hypercalciuria is a frequent abnormality in this setting, although asymptomatic. Therefore, it should not be considered as a limitation for high dose VD supplementation in this population. TRIAL REGISTRATION: EudraCT:2014-A01454-43 . Registered 29 august 2016.

Impact of pharmacist consultation at clinical trial inclusion: an effective way to reduce drug-drug interactions with oral targeted therapy.

PURPOSE: Pharmacist consultation is unfrequently performed in oncology clinical trials that include patients who often have many co-treatments increasing the risk of drug-drug interactions (DDI). The aim of this study was to determine whether best possible medication history (BPMH) by hospital pharmacist at inclusion and therapeutic drug monitoring could be used for DDI risk evaluation and for current oral targeted therapy management. METHODS: A prospective clinical trial (ALCINA 2, NCT04025541) was carried out in metastatic breast cancer cohort treated by palbociclib to conduct pharmacokinetics-toxicity correlation study. BPMH was prospectively performed by the hospital pharmacist at each trial inclusion, followed by a contact to the patient's community pharmacy to complete the collected data. Pharmacokinetic analysis was performed on blood samples collected at day 15 of cycle 1 of palbociclib treatment. RESULTS: Pharmacist interventions indicated that at inclusion, current medications were incomplete for 63% of the enrolled patients (32/51). It allowed the real-time management of high-risk DDI detected in third of patients. The palbociclib Ctrough geometric median (min-max) was significantly higher in cohort with potential DDI [106 ng/mL (66.7-113)], than cohort without potential DDI [70.1 ng/mL (54.1-89.7)], p = 0.0284. CONCLUSION: This is the first prospective study evaluating the relevance of proactive BPMH by pharmacist with contact to the community pharmacy during the inclusion step of a clinical trial to ensure the efficacy and safety of the investigated drug. This investigation was thus able to highlight the statistically significant impact of these DDI on palbociclib plasma concentration variation during the clinical trial. TRIAL REGISTRATION: Clinicaltrials.gov identifier NCT04025541.